The present invention relates to a production process and purification process of optically active 1-(fluoro- or trifluoromethyl-substituted phenyl)ethylamine that is an important intermediate of pharmaceuticals and agricultural chemicals.
Optically active 1-(fluoro- or trifluoromethyl-substituted phenyl)ethylamine is an important intermediate of pharmaceuticals and agricultural chemicals. The following technologies have been reported as production processes and purification processes of the optically active amine.
For example, although a production process of optically active 1-(3,5-bis-trifluoromethylphenyl)ethylamine, which is a compound in which two trifluoromethyl groups have been substituted, was reported in J. Am. Chem. Soc., 112, 5741 (1990), and was synthesized with reference to asymmetric reduction of oxime derivative described in J. Chem. Soc., Perkin Trans. 1, 2039 (1985), its chemical yield and optical purity were low at 15% and 71% ee(S), respectively.
In addition, a production process of optically active 1-(2-trifluoromethylphenyl)ethylamine (ortho-trifluoromethyl form), which is a compound in which one trifluoromethyl group has been substituted, was also reported in the above reference, and although it was synthesized by a similar procedure, its chemical yield and optical purity were low at 16% and 76% ee(S), respectively.
A production process of optically active 1-(3-trifluoromethylphenyl)ethylamine (meta-trifluoromethyl form) was reported in Japanese Unexamined Patent Publication No. 9-278718, and although optical resolution was carried out by 1-mandelic acid, the chemical yield and optical purity of the precipitated diastereomer salt crystals were low at 45% and 60% ee (S), respectively (the chemical yield and optical purity of the mother liquor and crystal washings were 55% and 50% ee (R), respectively). In addition, although it is also synthesized by a technique similar to the case of the ortho-trifluoromethyl form, the chemical yield and optical purity were low at 19% and 87% ee (S), respectively (J. Am. Chem. Soc., 112, 5741 (1990)).
A production process of optically active 1-(4-trifluoromethylphenyl)ethylamine (para-trifluoromethyl form) was reported in J. Am. Chem. Soc., 105, 1578 (1983), and although three times of recrystallization were carried out on crystals of a precipitated diastereomer salt in optical resolution by 1-N-acetylleucine, its chemical yield and optical purity were low at 19% and 60% ee(S), respectively. In addition, although this has also been synthesized according to a non-enzymatic enantioselective acylation reaction using a planar-chiral derivative of 4-pyrrolidinopyridine, and it has been reported that the non-reacted S form is concentrated by use of (xe2x88x92)-Ph-PPY*, its chemical yield and optical purity were not described (Chem. Commun., 2000, 119).
A production process of optically active 1-(4-fluorophenyl)ethylamine (para-fluoro form) is reported in Tetrahedron, 56, 6651 (2000), J. Chem. Soc., Perkin Trans. 2, 1339 (2000) and J. Chem. Soc., Perkin Trans. 2, 95 (1978), and although optical resolution was carried out by (S)-3xe2x80x2,4xe2x80x2-methylenedioxymandelic acid, (S)-2-naphthylglycolic acid and (+)-tartaric acid, respectively, in these processes, special resolving agents are required and the resolution efficiency was not always high.
As has been described above, it has not been possible in the prior art to produce optically active 1-(fluoro- or trifluoromethyl-substituted phenyl)ethylamine both efficiently and with high optical purity.
In addition, as the technical background of the present invention, there are provided asymmetric reduction of optically active N-(alkylbenzylidene)-xcex1-methylbenzylamines and their following hydrogenolysis.
To begin with, a description is provided of the former, asymmetric reduction. Although a comparatively large amount of research has been conducted on this type of diastereofacial selective 1,3-asymmetric reduction, examples of asymmetric reduction of optically active imine represented by the general formula [3], which is the target of the present invention, have not been reported, and in the case of asymmetric reduction using hydride reducing agents, since the effects of substitution position of the fluorine atom or trifluoromethyl group along with the number of substituted groups (n) on diastereofacial selectivity cannot be predicted at all, whether or not this is efficient as an industrial production process of the ant corresponding optically active 1-(fluoro- or trifluoromethyl-substituted phenyl)ethylamine has remained unknown.
As an example of a related technology, although an example of carrying out asymmetric reduction of an optically active imine of ortho position, in which R in the general formula [3] is a fluorine atom and n is 1, in a hydrogen atmosphere using a Raney nickel catalyst is reported in J. Fluorine Chem., 49, 67 (1990), the diastereofacial selectivity was extremely low at 37% de, and was not considered to be an efficient industrial production process.
Next, a description is provided of the latter hydrogenolysis. As is represented by the general formula [9]: 
(wherein, R represents an alkyl group, Ar1 and Ar2 represent aryl groups, and the asterisks (*) represent chiral carbon atoms), the product obtained by the above-mentioned asymmetric reduction has two similar xcex1-alkylaralkyl groups with respect to the nitrogen atom, and in the case of hydrogenolysis, which is a typical process for removing chiral auxiliary group, since only the chiral auxiliary group side (b) cannot be selectively cleaved, it was difficult to employ these series of technologies as a process for asymmetric synthesis of typical optically active xcex1-alkylbenzylamines.
In particular, since the optically active secondary amine represented by the general formula [4], which is a target of the present invention, has methyl groups for both of the alkyl groups, the steric bulkiness at the cleaved sites is nearly the same. In such cases, cleavage must be performed selectively by using the steric or electronic effects of the substitution groups on the aryl groups.
For example, it is reported in DE3819438 and Tetrahedron Lett., 30, 317 (1989) that, in the case of Ar2 having a plurality of electron donating groups such as methoxy groups (R is a methyl group, Ar1 is a phenyl group and the stereochemistry is Sxe2x80x94S in the above general formula [9]), cleavage occurs with complete positional selectivity at the chiral auxiliary group side (b) (selectivity (a:b) at the cleavage position is 0:100).
In addition, the case of Ar2 having an electron withdrawing group of chlorine or fluorine at position 2 (ortho position) (R is a methyl group, Ar1 is a phenyl group and the stereochemistry is Sxe2x80x94S in the above general formula [9]) is also reported in the above patent (DE3819438) and J. Fluorine Chem., 49, 67(1990), and in this case as well, cleavage is reported to occur selectively at the chiral auxiliary group side (b).
However, under conditions in which the 2-fluoro form (ortho-fluoro form) is subjected to hydrogenolysis by ammonium formate in the presence of a palladium/active carbon catalyst, the selectivity (a:b) at the cleavage position decreases to 11:89 as compared with the above case of Ar2 having electron donating groups, and in order to obtain the target optically active 1-(2-fluorophenyl)ethylamine with a high chemical purity, it was necessary to separate the (S)-xcex1-methylbenzylamine produced as a by-product by column chromatography, thereby preventing this from being an efficient industrial production process. In addition, although examples of the hydrogenolysis carried out in a hydrogen atmosphere in the presence of palladium/active carbon catalyst have also been indicated, since the amount of palladium metal used under the disclosed reaction conditions is extremely high at 2 wt %, and since the hydrogen pressure is also extremely high at 180 bar, these were not considered to be reaction conditions that can be used as an industrial production process.
Hydrogenolysis of optically active secondary amine represented by the general formula [4], which is the target of the present invention, has yet to be reported, the effects of substitution position of the fluorine atom or trifluoromethyl group along with number of substituted groups (n) on the selectivity (a:b) at the cleavage position cannot be predicted, and whether or not it is possible to efficiently convert to the corresponding optically active 1-(fluoro- or trifluoromethyl-substituted phenyl)ethylamine under reaction conditions that can be employed as an industrial production process has been unknown. In other words, even though position 2 (ortho position) is the closest to the cleavage position and is the substitution position that most easily imparts steric or electronic effects, under hydrogenolysis conditions that can be employed as an industrial production process, the selectivity (a:b) at the cleavage position is low, and when this is taken into consideration, as the substitution position of the fluorine atom or trifluoromethyl group moves away from the cleavage position, that selectivity is predicted to further decrease, and among the optically active secondary amines represented by the general formula [4] that are the target of the present invention in particular, in those position 3 (meta position) or position 4 (para position) compounds in which a is 1, hardly any selectivity (a:b) at the cleavage position can be expected, and it was unknown as to whether or not this was efficient as an industrial production process of the corresponding optically active 1-(fluoro- or trifluoromethyl-substituted phenyl)ethylamine.
As has been explained above, in the prior art, it was not possible to obtain optically active 1-(fluoro- or trifluoromethyl-substituted phenyl)ethylamine with high optical purity, industrially easily and efficiently.
The object of the present invention is to provide an industrially simple and efficient production process and purification process for obtaining an optically active 1-(fluoro- or trifluoromethyl-substituted phenyl)ethylamine having high optical purity.
As a result of earnest studies to solve the above problems, the present inventors showed that by dehydrating and condensing fluoro- or trifluoromethyl-substituted phenylmethyl ketone and optically active primary amine under acidic conditions, by asymmetrically reducing the resulting optically active imine using a hydride reducing agent, and particularly sodium borohydride, converting to an optically active secondary amine with a high degree of diastereofacial selectivity, and by subjecting the secondary amine, its inorganic salt or its organic salt to hydrogenolysis while heating, the amount of metal catalyst used and hydrogen pressure can be significantly reduced and the reaction proceeds with complete selectivity at the cleavage position. More specifically, by conducting hydrogenolysis while heating at 40xc2x0 C. or higher using a group VIII metal catalyst, and particularly a palladium catalyst, at 0.5 wt % or less when converted as metal in a hydrogen atmosphere of 2 MPa or lower, it was found that optically active 1-(fluoro- or trifluoromethyl-substituted phenyl)ethylamine can be produced in an industrially simple and efficient manner at high optical purity.
In addition, it was found that by converting the optically active secondary amine of the synthetic intermediate obtained by asymmetric reduction, or optically active 1-(3,5-bis-trifluoromethylphenyl)ethylamine, which is one of the target compounds, to the salt of an inorganic acid or organic acid, and particularly hydrochloric acid, hydrobromic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, optically active mandelic acid or optically active tartaric acid, followed by purification by recrystallization, optically active 1-(fluoro- or trifluoromethyl-substituted phenyl)ethylamine can be purified in an industrially simple and efficient manner to an even higher optical purity, thereby leading to completion of the present invention.
The process of the present invention is represented by the following Scheme 1. 
Namely, the present invention is a process for producing an optically active 1-(fluoro- or trifluoromethyl-substituted phenyl)ethylamine represented by the general formula [5]: 
(wherein, R represents a fluorine atom or trifluoromethyl group, n represents 1 to 5, and it takes an arbitrary substitution position, except for the ortho position when R is a fluorine atom and n is 1, and the asterisk (*) represents a chiral carbon) by asymmetrically reducing an optically active imine represented by the general formula [3]: 
(wherein, R represents a fluorine atom or trifluoromethyl group, n represents 1 to 5, and it takes an arbitrary substitution position, except for the ortho position when R is a fluorine atom and n is 1, Ar represents a phenyl group or 1- or 2-naphthyl group, and the asterisk (*) represents a chiral carbon) using a hydride reducing agent, converting to an optically active secondary amine represented by the general formula [4]: 
(wherein, R represents a fluorine atom or trifluoromethyl group, n represents 1 to 5, and it takes an arbitrary substitution position, except for the ortho position when R is a fluorine atom and n is 1, Ar represents a phenyl group or 1- or 2-naphthyl group, and the asterisks (*) represent chiral carbons), and subjecting the secondary amine, its salt of an inorganic acid or its salt of an organic acid to hydrogenolysis.
In addition, the present invention is a purification process characterized in that an optically active secondary amine represented by the general formula [4]: 
(wherein, R represents a fluorine atom or trifluoromethyl group, n represents 1 to 5, and it takes an arbitrary substitution position, except for the ortho position when R is a fluorine atom and n is 1, Ar represents a phenyl group or 1- or 2-naphthyl group, and the asterisks (*) represent chiral carbons) is converted to a salt of an inorganic acid or organic acid, followed by purification by recrystallization.
In addition, the present invention is a purification process characterized in that an optically active 1-(3,5-bis-trifluoromethylphenyl)ethylamine represented by the formula [6]: 
(wherein, the asterisk (*) represents a chiral carbon) is converted to the salt of an inorganic acid or organic acid followed by purification by recrystallization.
In addition, the present invention is an optically active imine represented by the general formula [7]: 
(wherein, R represents a fluorine atom or trifluoromethyl group, n represents 1 to 5, and it takes an arbitrary substitution position, except for the ortho position and the para position when R is a fluorine atom and n is 1, Ar represents a phenyl group or 1- or 2-naphthyl group, and the asterisk (*) represents a chiral carbon).
In addition, the present invention is an optically active secondary amine represented by the general formula [4]: 
(wherein, R represents a fluorine atom or trifluoromethyl group, n represents 1 to 5, and it takes an arbitrary substitution position, except for the ortho position when R is a fluorine atom and n is 1, Ar represents a phenyl group or 1- or 2-naphthyl group, and the asterisks (*) represent chiral carbons).
In addition, the present invention is an optically active 1-(fluoro-substituted phenyl)ethylamine represented by the general formula [8]. 
(wherein, n represents 1 to 5, and it takes an arbitrary substitution position, except for the ortho position and the para position when n is 1, and the asterisk (*) represents a chiral carbon).
In addition, the present invention is a salt of an inorganic acid or organic acid of an optically active secondary amine represented by the general formula [4]: 
(wherein, R represents a fluorine atom or trifluoromethyl group, n represents 1 to 5, and it takes an arbitrary substitution position, except for the ortho position when R is a fluorine atom and n is 1, Ar represents a phenyl group or 1- or 2-naphthyl group, and the asterisks (*) represent chiral carbons).
In addition, the present invention is a salt of an inorganic acid or organic acid of an optically active 1-(3,5-bis-trifluoromethylphenyl)ethylamine represented by the formula [6]: 
(wherein, the asterisk represents a chiral carbon).
In addition, the present invention is the above salt wherein the organic acid comprises p-toluenesulfonic acid, optically active mandelic acid or optically active tartaric acid.